Mercury and Alzheimers Disease: HG(II) Ions Display Specific Binding to the Amyloid-Beta Peptide and Modulate its Aggregation

Abstract

Increasing evidence connects Alzheimer's disease (AD) to metal exposure. Aberrant metal concentrations are observed in AD brains, but the role of metals in AD pathology remains unresolved. Animal models exposed to mercury display the typical pathological signs of AD, and many studies (but not all) indicate elevated mercury levels in brain tissue of AD patients. At a molecular level, however, no mechanisms have been described that would link mercury to AD pathogenesis. The pathological hallmark of AD brains is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils. Previous research has shown that Aβ peptide aggregation and fibrillation can be modulated by specific binding between Aβ and metal ions such as Cu(II) and Zn(II). Here, we study in vitro the molecular interactions between Aβ(1-40) and Hg(II) ions. NMR spectroscopy results show that Hg(II) ions bind the N-terminal part of the Aβ(1-40) peptide, likely via the same ligands that bind Cu(II) and Zn(II) ions, i.e. histidines H6, H13, and H14. Fluorescence quenching of Aβ residue Y10 by Hg(II) ions indicates the apparent Hg(II)/Aβ dissociation constant to be around 1-3 µM. Fluorescence spectroscopy and solid state atomic force microscopy (AFM) show a concentration-dependent effect of Hg(II) ions on Aβ fibrillation, which is completely inhibited at a 1:1 Aβ:Hg(II) ratio. Thus, together with e.g. Cu(II), Fe(II), Mn(II), Pb(IV) and Zn(II), the Hg(II) ion belongs to a family of metal ions that modulate Aβ aggregation by binding to specific Aβ ligands. This indicates that AD metal chemistry is more complex than previously considered, and may have implications for AD pathology and pathogenesis, especially as in most countries mercury continues to be an important environmental contaminant.